Immune-related Response Research Articles

17β-Estradiol and 17α-Ethinyl Estradiol Exhibit Immunologic and Epigenetic Regulatory Effects in NZB/WF1 Female Mice.

17α-Ethinyl estradiol (EE), a synthetic analog of natural estrogen 17β-estradiol (E2), is extensively used in hormonal contraceptives and estrogen replacement therapy, and it has also been found in sewage effluents. Given that E2 is a well-known immunomodulator, surprisingly there has been only limited information on the cellular and molecular immunologic consequences of exposure to EE. To address this fundamental gap, we directly compared the effects of EE with E2 on splenic leukocytes of New Zealand Black × New Zealand White F1 progeny (NZB/WF1) mice during the preautoimmune period. We found that EE and E2 have common, as well as distinctive, immunologic effects, with EE exposure resulting in more profound effects. Both EE and E2 increased numbers of splenic neutrophils, enhanced neutrophil serine proteases and myeloperoxidase expression, promoted the production of nitric oxide and monocyte chemoattractant protein-1, and altered adaptive immune T cell subsets. However, activation of splenic leukocytes through the T cell receptor or Toll-like receptor (TLR)4 revealed not only common (IL-10), but also hormone-specific alterations of cytokines (IFNγ, IL-1β, ΤΝFα, IL-2). Furthermore, in EE-exposed mice, TLR9 stimulation suppressed IFNα, in contrast to increased IFNα from E2-exposed mice. EE and E2 regulated common and hormone-specific expression of immune-related genes. Furthermore, EE exposure resulted in more marked alterations in miRNA expression levels than for E2. Only EE was able to reduce global DNA methylation significantly in splenic leukocytes. Taken together, our novel data revealed that EE and E2 exposure confers more similar effects in innate immune system-related cell development and responses, but has more differential regulatory effects in adaptive immune-related cell development and responses.

Efficacy and safety of BRAF inhibitors and anti-CTLA4 antibody in melanoma patients-real-world data.

In the management of melanoma, BRAF inhibitors yield fast disease control; however, the duration of response does not last very long. Ipilimumab-an anti-CTLA4 antibody on the other hand-provides longer-lasting results of treatment but achieves less favorable responses. The aim of this study was to assess the efficacy and safety of novel drugs for advanced melanoma in daily routine practice. A retrospective observational study was conducted on all Polish patients (1170 patients), diagnosed with advanced metastatic melanoma, treated with the following drugs: vemurafenib, dabrafenib, and ipilimumab. The antitumor efficacy of these agents was retrospectively assessed by Response Evaluation Criteria in Solid Tumors in the case of BRAF inhibitors and by Immune-Related Response Criteria in the case of ipilimumab therapy. Adverse events were assessed in relation to the morphologic parameters of blood, nephrotoxicity, and hepatotoxicity. The overall response to treatment with BRAF inhibitors (vemurafenib and dabrafenib) was similar with a slightly better outcome in the group treated with vemurafenib. Compared to clinical trials, the objective response rate was slightly worse for both BRAF inhibitors (30% and 42% for dabrafenib and vemurafenib, respectively), as well as the immune-related response for ipilimumab (1%). There was no significant difference in patient's response rates regardless of what lines of treatment (first, second, or next) vemurafenib was applied in. A few severe adverse events (mostly anemia and hyperbilirubinemia) were observed during treatment. The lack of evidence in responses observed regardless of what line of treatment vemurafenib was applied in suggests there is no clinical reason for restricting BRAF inhibitors to only the first line of therapy. Our study confirms that novel agents brought about a major advancement in the management of melanoma. In line with literature, BRAF inhibitors and ipilimumab significantly improved the antitumor response rate with manageable adverse events.

P3.04-20 Correlation of Immune-Related Adverse Events and Response from Immune Checkpoint Inhibitors in Patients with Advanced NSCLC

P3.04-20 Correlation of Immune-Related Adverse Events and Response from Immune Checkpoint Inhibitors in Patients with Advanced NSCLC

Initial Clinical Experience of Nivolumab for Metastatic Renal Cell Carcinoma

Nivolumab was approved as a new agent for advanced renal cell carcinoma (RCC) in Japan on September 2016. Nivolumab is an immune checkpoint inhibitor that activates the cytotoxic immune response and has exerted antitumor effects in a mechanism different from other available molecular targeted agents. Therefore, its response pattern, efficacy and adverse events are different from those of the molecular targeted agents for RCC. Here, we report our initial clinical experience with nivolumab. From December 2016 to September 2017, we applied nivolumab to 7 patients with metastatic RCC. The most common metastatic site was the lungs, followed by lymph nodes, bones and brain. According to the immune-related response criteria, the efficacy was stable disease in 2 patients and progressive disease in 5 patients. In 5 cases with multiple metastases, responses differed with the site of metastasis. The response was best in lung metastasis and worst in brain metastasis. Six cases had minor adverse events. In two cases, we discontinued administration of nivolumab temporarily. The patients recovered completely and we considered nivolumab effective and safe for treatment of metastatic RCC.

PD-L2 Expression as a Potential Predictive Biomarker for the Response to Anti-PD-1 Drugs in Patients with Non-small Cell Lung Cancer.

To investigate the role of programmed cell death-ligand 2 (PD-L2) expression as a predictive biomarker for response to anti-programmed cell death-1 (PD-1) drugs in patients with non-small cell lung cancer (NSCLC). Ten patients who had undergone curative lung resection and received the anti-PD-1 drugs for the recurrence were enrolled. The cut-off value for PD-L2 (antibody clone 176611) expression on tumor cells was set at 50%. Tumor response was evaluated according to immune-related response criteria. Seven patients (70.0%) were positive for PD-L2. The response rates were 28.6% (2/7) and 33.3% (1/3) in patients with PD-L2-positive and PD-L2-negative NSCLC, respectively. Disease control was obtained in 2 patients despite the programmed cell death-ligand 1 (PD-L1)-negativity (antibody clone 22C3: 0%, antibody clone SP142: 0%), and these tumors expressed PD-L2 (≥1%). PD-L2 expression may be a target of immunotherapy in patients with PD-L1-negative NSCLC.

Expression of infection-related immune response in European sea bass (Dicentrarchus labrax) during a natural outbreak from a unique dinoflagellate Amyloodinium ocellatum

In the Mediterranean area, amyloodiniosis represents a major hindrance for marine aquaculture, causing high mortalities in lagoon-type based rearing sites during warm seasons. Amyloodinium ocellatum (AO) is the most common and important dinoflagellate parasitizing fish, and is one of the few fish parasites that can infest several fish species living within its ecological range. In the present study, A. ocellatum was recorded and collected from infected European sea bass (Dicentrarchus labrax) during a summer 2017 outbreak in north east Italy. Histological observation of infected ESB gill samples emphasized the presence of round or pear-shaped trophonts anchored to the oro-pharingeal cavity. Molecular analysis for small subunit (SSU) rDNA of A. ocellatum from gill genomic DNA amplified consistently and yielded 248 bp specific amplicon of A. ocellatum, that was also confirmed using sequencing and NCBI Blast analysis. Histological sections of ESB gill samples were addressed to immunohistochemical procedure for the labelling of ESB igm, inos, tlr2, tlr4, pcna and cytokeratin. Infected gills resulted positive for igm, inos, pcna and cytokeratin but negative to tlr-2 and tlr-4. Furthermore, ESB immune related gene response (innate immunity, adaptive immunity, and stress) in the course of A. ocellatum infection using quantitative polymerase chain reaction (qpcr) for infected gills and head kidney was analysed. Among the twenty three immune related gene molecules tested, cc1, il-8, il-10, hep, cox-2, cla, cat, casp9, and igt were significantly expressed in diseased fish. Altogether, these data on parasite identification and expression of host immune-related genes will allow for a better understanding of immune response in European sea bass against A. ocellatum and could promote the development of effective control measures.

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)

BackgroundNeoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methodsThe first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic ‘tumor’ measurements were also assessed. ResultsWe found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation—dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death—cholesterol clefts; and (iii) tissue repair—neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P<0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop ‘Immune-Related Pathologic Response Criteria’ (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%–29%) versus 10% (0%–58%), P=0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P=0.002). ConclusionsirPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

Systemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila

Drosophila hemocytes are akin to mammalian myeloid blood cells that function in stress and innate immune-related responses. A multi-potent progenitor population responds to local signals and to systemic stress by expanding the number of functional blood cells. Here we show mechanisms that demonstrate an integration of environmental carbon dioxide (CO2) and oxygen (O2) inputs that initiate a cascade of signaling events, involving multiple organs, as a stress response when the levels of these two important respiratory gases fall below a threshold. The CO2 and hypoxia-sensing neurons interact at the synaptic level in the brain sending a systemic signal via the fat body to modulate differentiation of a specific class of immune cells. Our findings establish a link between environmental gas sensation and myeloid cell development in Drosophila. A similar relationship exists in humans, but the underlying mechanisms remain to be established.

Abstract LB-154: Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small cell lung carcinoma (NSCLC): A proposal for quantitative immune-related pathologic response criteria (irPRC)

Abstract There is great interest in using PD-(L)1 blockading drugs as neoadjuvant therapy for patients with resectable NSCLC. Early results demonstrated a 45% (9/20) major pathologic response (MPR) rate in patients with Stage I-III NSCLC after receiving nivolumab (NCT02259621). Major pathologic response (MPR) criteria were developed in the context of cytotoxic chemotherapy, defined as ≤10% residual viable tumor cells (RVT). The features of immune-mediated tumor regression following anti-PD-1 have yet to be described. We reviewed H&amp;E-stained slides from resection specimens in 19 patients treated with neoadjuvant nivolumab [n=9 MPR, n=3 partial responders, n=7 non-responders (&amp;gt;70% RVT)] to identify histopathologic features of immune-mediated tumor regression. Specimens were assessed for immune characteristics (tumor infiltrating lymphocyte (TIL) and macrophage density, and presence/absence of, lymphoid aggregates, tertiary lymphoid structures (TLS), dense plasma cell infiltrates, neutrophils, giant cells, etc.) and non-immune features (necrosis, hemosiderin, hyalinized and proliferative fibrosis). We found that immune-mediated tumor regression is characterized by a fibroinflammatory stroma with features of (1) immune activation, including dense TIL and macrophages, TLS, and granulomas; (2) massive [tumor] cell death, including cholesterol clefts and giant cells; and (3) tissue repair, including neovascularization and proliferative fibrosis (each enriched in MPR vs. non-responders, Fisher's exact test p&amp;lt;0.05). An “outside-in” pattern of regression was noted, which has important implications for defining total tumor bed area. As such, we propose “Immune-Related Pathologic Response Criteria” (irPRC), with tumor bed defined by RVT + necrosis + surrounding fibroinflammatory stroma. The areas of each are summed across all slides to calculate %RVT (RVT area/tumor bed area). This differs from chemotherapy MPR criteria, where %RVT is determined for each slide and then averaged, and the distinct fibroinflammatory regression stroma and peripheral regression bed are not acknowledged. The surgical resection specimens were then evaluated by four independent pathologists blinded to response to assess inter-observer variability. Compared to %RVT using chemotherapy criteria, irPRC had improved inter-observer variability [median per-case %RVT variability 5% (0-29%) vs. 10% (0-58%), paired t test p=0.007] and a two-fold decrease in median standard deviation across pathologists within a sample (4.6 vs 2.2, F-test p=0.002). We propose irPRC to standardize pathologic assessment of immune-mediated tumor regression and immunotherapeutic efficacy. Long-term follow up is needed to determine the reliability of irPRC as a surrogate for clinical outcomes such as recurrence-free and overall survival. Citation Format: Tricia R. Cottrell, Julie E. Stein, Jamie E. Chaft, Elizabeth D. Thompson, Natasha Rekhtman, Valsamo Anagnostou, Kellie N. Smith, Amy S. Duffield, Robert A. Anders, James M. Isbell, David R. Jones, Jonathan D. Cuda, Richard Battafarano, Stephen C. Yang, Peter B. Illei, Edward Gabrielson, Frederic Askin, Moises Velez, Matthew D. Hellmann, Jennifer L. Sauter, Ludmila Danilova, Victor E. Velculescu, Jedd D. Wolchok, Suzanne L. Topalian, Julie R. Brahmer, Drew M. Pardoll, Ashley Cimino-Mathews, Patrick M. Forde, Janis M. Taube. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small cell lung carcinoma (NSCLC): A proposal for quantitative immune-related pathologic response criteria (irPRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-154.

Abstract CT053: Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC and MSI-H endometrial cancer

Abstract Introduction: TSR-042 is a humanized monoclonal antibody targeting programmed death (PD)-1, effectively blocking interaction with its ligands PD-L1 and PD-L2. TSR-042 is being evaluated in patients (pts) with advanced solid tumors in the ongoing phase 1 GARNET trial (NCT02715284). Weight based dose escalation (Part 1) and fixed-dose safety studies (Part 2A) have been completed,1 and the study is currently enrolling pts with specific tumor types into expansion cohorts. Here, we present safety and efficacy data from the microsatellite instability-high (MSI-H) endometrial cancer (EC) and non-small cell lung cancer (NSCLC) cohorts, as well as pharmacokinetic (PK) and receptor occupancy (RO) characterization at the recommended phase 2 dose (RP2D). Methods/Procedures: 30 NSCLC pts and 19 MSI-H EC pts with previously treated recurrent or advanced disease were enrolled; median number of prior lines of therapy for metastatic disease was 1.0 for both cohorts. MSI status for EC pts was determined centrally using a next generation sequencing-based assay. Key exclusion criteria included prior therapy with agents targeting anti-PD-1, PD-L1, or PD-L2, and uncontrolled CNS metastases. Pts were treated at the R2PD of TSR-042: 500 mg Q3W for the first 4 cycles and 1000 mg Q6W thereafter. Serum and PBMCs were collected for PK and RO analyses, respectively. Antitumor activity was assessed by investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). RO was assessed using a CD3+ binding assay (direct receptor occupancy).1 Results: Among the 30 NSCLC and 19 MSI-H EC pts, 42 (85.7%) pts reported ≥1 adverse event (AE), with grade ≥3 AEs reported in 13/49 (26.5%) pts. The most common AEs were diarrhea and nausea (11 pts each), arthralgia and fatigue (9 pts each), and cough, decreased appetite, and dyspnea (7 pts each). 25/49 (51.0%) pts reported treatment-related AEs; 11/49 (22.4%) pts had serious AEs; 1 case of grade 3 fatigue and 1 case of grade 3 leukopenia and grade 3 neutropenia were deemed treatment-related. 21 NSCLC and 11 MSI-H EC pts had at least 1 tumor assessment. Among NSCLC pts, 7/21 (33.3%) had a partial response (irPR; confirmed and unconfirmed), and 6/21 (28.6%) had stable disease (irSD); among MSI-H EC pts, 4/11 (36.4%) had irPR, and 2/11 (18.2%) had irSD. TSR-042 demonstrated dose-proportional PK. The maximal achievable RO was observed in pts treated at the RP2D, consistent with the results reported for Parts 1 and 2A.1 Conclusions: These results indicate clinical benefit of TSR-042 in previously treated NSCLC and MSI-H EC patients, with a safety profile similar to other PD-1 inhibitors. PK results were consistent across all patients evaluated and show that maximal achievable receptor occupancy was attained at the RP2D. 1. Sachdev JC et al. Ann Oncol. 2017(suppl 5):28:420;1185P Citation Format: Victor Moreno, Maria-Pilar Barretina-Ginesta, Wei Guo, Sharon Lu, David Jenkins, Kristen McEachern, Vienna Reichert, Steven Dunlap, Ellie Im, Lucy Gilbert, Ana Oaknin, Charles Leath, III, Janakiraman Subramanian. Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC and MSI-H endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT053.

Abstract 3679: PD-L1 driven excluded phenotype in melanoma

Abstract Background: The excluded phenotype has been previously described by the presence of abundant immune cells that do not penetrate the parenchyma of these tumors but instead are retained in the stroma that surrounds nests of tumor cells. These features support a pre-existing anti-tumor immune-related response, but the details of this mechanism are not well elucidated. Methods: 300 formalin-fixed, paraffin-embedded (FFPE) metastatic cutaneous melanoma samples were evaluated by the RNA-seq component of a comprehensive immune profile panel to measure transcript levels of immune-related genes. Resultant data was QC filtered, normalized and ranked based on an assorted reference population of various tumor types. The expression of PD-L1 on the surface of tumor cells was assessed in tumor samples by means of an automated IHC assay (28-8, Dako). A tumor was considered PD-L1 positive if ≥1% of viable tumor cells exhibited complete circumferential or partial linear plasma membrane staining at any intensity. Excluded pattern of T-cell infiltration was defined by CD8 immunohistochemistry by the following definition: Restriction of more than 95% of all CD8+ T-cells present in a tumor to the periphery or interstitial stromal areas and not actively invading nest or groups of neoplastic cells. Results: The excluded phenotype was identified in 34 of 300 (11%). PD-L1 by IHC was positive (≥1%) in the neoplastic cases in 16 of 34 (47%) cases. Membranous staining in immune cells was identified in only 3 of 34 (9%) cases, but was present in &amp;gt;90% of all cases in a non-membranous pattern. In more than one-half of all cases the non-membranous pattern of PD-L1 IHC staining was restricted to the excluded TILs. Higher expression of PD-L1 by RNA-seq was associated with this excluded PD-L1 pattern of staining. Conclusion: In 300 metastatic cutaneous melanoma cases we demonstrated that the excluded phenotype is frequent and represents ~10% of all cases. Moreover, in a significant number of excluded cases expression of PD-L1 by IHC was distinctly limited to the excluded TILs. This finding would support a unique mechanism of PD-L1 anti-tumor immune-related response that needs further investigation. Citation Format: Carl Morrison, Jeffrey Conroy, Mary Nesline, Sean Glenn, Blake Burgher, Maochun Qin, Jonathan Andreas, Vincent Giamo, Felicia L. Lenzo, Angela Omilian, Wiam Bshara, Antonios Papanicolau-Sengos, Yirong Wang, Marc Ernstoff, Mark Gardner, Sarabjot Pabla. PD-L1 driven excluded phenotype in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3679.

Abstract CT059: Epigenetic tumor remodelling to improve the efficacy of immune checkpoint blockade: the NIBIT-M4 clinical trial

Abstract Introduction: The anti-CTLA-4 monoclonal antibody (mAb) ipilimumab (Ipi) has firstly shown the therapeutic potential of targeting immune checkpoints in metastatic melanoma (MM) patients (pts), though with limited objective clinical responses, ranging from 10 to 13% (Hodi, NEJM 2010; Ascierto, TLO 2017). Targeting of CTLA-4 is of interest due to its role in the priming phase of the immune response; thus, anti-CTLA-4 mAb are being tested in different combinations to improve their clinical efficacy also by overcoming tumor resistance to treatment. We have thoroughly demonstrated that epigenetic remodelling of cancer cells with DNA hypomethylating agents (DHA) improves tumor immunogenicity and immune recognition (Maio M, CCR 2015). These findings identified DHA as highly intriguing “partner agents” to improve the therapeutic index of checkpoint blockers, including CTLA-4 mAb. This hypothesis is being tested in the ongoing NIBIT-M4 study (NCT02608437). Methods: The NIBIT-M4 is a phase 1b, dose-escalation study sequencing treatment-naïve/pre-treated, unresectable Stage III/IV MM pts, with the next generation DHA guadecitabine followed by Ipi. The dose escalation follows a 3+3 design: guadecitabine (at 30, 45 or 60 mg/m2) is administered s.c. on Week (W) 0, 3, 6, 9, days 1-5 and Ipi i.v. at 3 mg/kg on W1, 4, 7 and 10 q21d. Tumor assessment per immune-related response criteria is performed at screening (W0), W12, 18, 24 and q12 weeks. Patients-wise genome-wide methylation, RNA sequencing, whole-exome sequencing, and immunohistochemistry (IHC) analyses were performed on tumor samples collected at W0, 4 and 12. Canonical pathways and upstream regulators were investigated with IPA. Preliminary results: Fourteen out of the 19 planned pts have been enrolled so far, with no dose limiting toxicities. Among the 11 evaluable pts, the objective response rate is 27%. A reduction in tumor CpG sites methylation, from W0 (median 81.18%) to W4 (median 76.54%) and W12 (median 76.89%), was identified in the initial 8 pts enrolled. Transcriptomic analyses identified 3,897 ± 3,577 and 5,414 ± 3,569 differentially expressed genes (DEG) (q &amp;lt; 0.05, and absolute log2-fold-change &amp;gt;1.0) at W4 and W12 compared to W0, respectively. Among the 137 pathways that were significantly modulated in all tumor samples at either W4 and/or W12, the most frequently activated ones were immune related (i.e., Th1 and Th2, iCOS-iCOSL and CD28 Signaling in T Helper Cells, and Interferon (IFN) Signaling). In addition, the top predicted upstream regulators were genes involved in the interferon IFN pathway (i.e., IFNG, STAT1, IRF7, IFNA2, IRF1). Though limited by the current sample size investigated, a greater number of significantly (p&amp;lt;0.05) activated immune-related pathways was identified in tumors of responder vs non-responder pts at W4 and/or W12 compared to W0. Quantitative IHC analyses revealed higher CD8+ and PD1+ cell densities in the tumor core of post-treatment biopsies of responder vs non-responder pts. Conclusions: Epigenetic tumor immune-remodeling seems to be a promising strategy to improve the efficacy of CTLA-4 blockade, to be further pursued also with other immunomodulating mAb. *AMDG and AC equally contributed. Citation Format: Anna M. Di Giacomo, Alessia Covre, Francesca Finotello, Dietmar Rieder, Luca Sigalotti, Carolina Fazio, Ornella Cutaia, Christoph Bock, Florent Petitprez, Laetitia Lacroix, James N. Lowder, Wolf H. Fridman, Catherine Sautès-Fridman, Zlatko Trajanoski, Michele Maio. Epigenetic tumor remodelling to improve the efficacy of immune checkpoint blockade: the NIBIT-M4 clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT059.

FcγRI (CD64) contributes to the severity of immune inflammation through regulating NF-κB/NLRP3 inflammasome pathway

AimsFcγ receptor I (FcγRI/CD64) that is restrictedly expressed on monocytes and macrophages, acts as the single high-affinity receptor of immunoglobulin G (IgG) in human. The expression of FcγRI is positively correlated with immune inflammation. The primary aim of this study was to explore the effects of FcγRI expression on immune-related inflammatory response and investigate the potential mechanisms. Main methodsFcγRI-expressing Ba/F3 cells are the ideal models for evaluating the functions of FcγRI. Nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome-associated protein expressions and inflammatory cytokine (IL-1β and IL-18) release were detected in the presence or absence of NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). Besides, the effects of FcγRI on the activation of the NLRP3 inflammasomes were also investigated in THP-1 macrophages deficient for FcγRI. Key findingsFcγRI-expressing Ba/F3 cells appeared increased NLRP3 inflammasome formation and IL-1β and IL-18 release via activating NF-κB signaling. Interestingly, this alteration could be reversed in THP-1 macrophages after FcγRI was silenced. SignificanceThese results indicated that FcγRI functioned as a regulator for immune inflammation via acceleration of NF-κB regulating NLRP3 inflammasome signaling.

Evaluation criteria for tumor efficacy in the times of immunotherapy

With the advent of the times of immunotherapy and the emergence of a variety of unconventional response patterns such as delayed response and pseudo-progressive disease, a variety of immune-related efficacy evaluation criteria such as immune-related response criteria, immune-related response evaluation criteria in solid tumor and immune response evaluation criteria in solid tumor have been proposed successively. The evaluation principles and judgment results of these criteria are distinctly different from the traditional response evaluation criteria. In particular, the newly proposed immune response evaluation criteria in solid tumor introduces two new concepts of unconfirmed progressive disease and confirmed progressive disease and provides a new response evaluation model for solid tumors, which is expected to provide solutions to some of the most urgent clinical problems under the times of cancer immunotherapy. Key words: Neoplasms; Immunotherapy; Response evaluation; Immune response evaluation criteria in solid tumors

FDA analysis of pembrolizumab trials in multiple myeloma: Immune related adverse events (irAEs) and response.

8008Background: Development of irAEs with checkpoint inhibition may be associated with response in some disease settings. Methods: We evaluated overall survival (OS), safety and objective response ...

Immune-related expression profiles and sunitinib response in metastatic clear cell renal cell carcinoma (ccRCC).

e16579Background: Antiangiogenic drugs, such as sunitinib (SU), can modulate the immune system through the inhibition of VEGFA decreasing the MDSC and Treg infiltration and preventing T cell anergy...

5-year survival outcomes in patients (pts) with advanced melanoma treated with pembrolizumab (pembro) in KEYNOTE-001.

9516 Background: Pembro has demonstrated robust antitumor activity and safety in several studies of advanced melanoma, including KEYNOTE-001, -002, and -006. Here, we describe the 5-year outcomes for all pts and for those who were treatment naive in the phase 1b KEYNOTE-001 study (NCT01295827). Methods: Pts aged ≥18 y with previously treated or treatment-naive, advanced or metastatic melanoma received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W until disease progression, intolerable toxicity, or pt/investigator decision to withdraw. The Kaplan-Meier method was used to estimate OS and PFS. ORR and PFS were based on immune-related response criteria by investigator assessment. Data cutoff was Sep 1, 2017. Results: KEYNOTE-001 enrolled 655 pts (151 treatment naive; 504 previously treated). After a median follow-up of 55 mo (range, 48-69), 35 pts are on pembro treatment. 63% (n = 412) of all pts died. The estimated 5-year OS rate was 34% in all pts and 41% in treatment-naive pts, similar to the 4-year rates of 38% and 48%, respectively. Median OS was 23.8 mo (95% CI, 20.2-30.4) in all pts and 38.6 mo (95% CI, 27.2-NR) in treatment-naive pts. 5-year PFS rates were 21% in all pts and 29% in treatment-naive pts; median PFS was 8.3 mo (95% CI, 5.8-11.1) and 16.9 mo (95% CI, 9.3-35.5) in all pts and treatment-naive pts, respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cutoff; the longest response observed in all pts was ongoing at 66 mo. Treatment-related AEs (TRAEs) occurred in 86% (n = 562) of pts, including 17% (n = 114) with grade 3/4 TRAEs and 7.8% (n = 51) who discontinued because of a TRAE. Conclusions: Pembro provides a 5-year OS rate of 34% in pts with previously treated and treatment-naive advanced melanoma, with a 5-year OS rate of 41% in treatment-naive pts. These data, representing the longest follow-up for pembro to date in any cancer, confirm the durable antitumor activity and tolerability of pembro in advanced melanoma. Clinical trial information: NCT01295827.

Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study

Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma. In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients. From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines. The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.

Radiologic Pseudoprogression during Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer

Anti-programmed cell death protein 1 (PD-1) therapy can lead to unconventional tumor responses, including radiologic pseudoprogression. Here we havedetermined the real-world incidence of radiologic pseudoprogression in advanced NSCLC and compared radiologic response criteria for assessment of disease response. The electronic medical records of all patients with NSCLC who were receiving anti-PD-1 therapy at our institution over a 3-year period were retrospectively reviewed, and patients with clinically suspected radiologic pseudoprogression were identified. Patients without available follow-up imaging or clinical data were excluded. Imaging examinations were then analyzed to determine whether progression was confirmed on subsequent reimaging. Assessments of tumor response by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (RECIST 1.1), the unidimensional immune-related response criteria (iRRC), and the iRECIST criteria for all patients were performed and compared. A total of 228 consecutive patients began receiving anti-PD-1 therapy over a 3-year period. Of the 166 of these patients who were evaluable, most (80%) received nivolumab. Fifteen patients (9%) were clinically suspected of having radiologic pseudoprogression on account of tumor enlargement and/or development of new lesions on computed tomography images during the first 4 to 6 weeks of therapy, and they continued receiving anti-PD-1 therapy. Three of these patients (2%) demonstrated evidence of radiologic pseudoprogression at first reimaging. The iRRC and immune RECIST criteria were more accurate in classifying radiologic pseudoprogression as nonprogression; none of the three cases were deemed progression by the iRRC or immune RECIST, whereas all three cases were determined to be progression according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Radiologic pseudoprogression is a clinical challenge but an uncommon occurrence in patients with NSCLC who are receiving anti-PD-1 therapy.

Pushing the limits of immune-related response: a case of \u201cextreme pseudoprogression\u201d

The advent of immune checkpoint targeted immunotherapy has seen a spectrum of immune-related phenomena in both tumor responses and toxicities. We describe a case of pseudoprogression that pushes the limits of immune-related response criteria and challenges the boundaries and definitions set by trial protocols. A middle-aged man with conventional clear cell renal cell carcinoma (RCC) had received multiple prior systemic treatments including vascular endothelial growth factor receptor tyrosine kinase inhibitors, as well as multiple surgeries and radiotherapy treatments. He was eventually started on nivolumab—the anti-programmed death receptor-1 monoclonal antibody approved for the treatment of advanced RCC. Clinical deterioration was observed soon after a 100 mg dose of nivolumab, with onset of acute renal failure and declining performance status. Radiologic progression was documented in multiple sites including worsening tumor infiltration of his residual kidney. The patient was on palliative treatment and visited by the home hospice team in an end-of-life situation. The patient unexpectedly improved and went on to achieve a durable tumor response. The case is illustrative of an extreme manifestation of pseudoprogression, and impels us to probe the assumptions and controversies surrounding this phenomenon.